If
a pandemic does come--as most scientists believe it will, despite
our best efforts--there will be an urgent need to support responses
at the community level. Like politics, all infectious diseases start locally.
As
generous as the
President's proposed plan may be for developing drugs and vaccines
against pandemic infectious diseases, primarily influenza, it has only
a small portion,
$500 million, for strengthening public health responsiveness in the 50
states. Howard Koh, former commissioner of Public Health for the Commonwealth
of
Massachusetts and head of our Division of Public Health Practice, with
support from the CDC,
has created a Center for Public Health Preparedness. David Gergen of Harvard's
Kennedy School of Government, working with the HSPH Center's Leonard
Marcus, has launched a program for national leadership training known as
the National
Preparedness Leadership Initiative. These programs are providing the best
information we have at Harvard University for equipping government officials
with the leadership
skills they need to deal with emergencies and pandemics.

VACCINES AS CENTERPIECES
According to official Department of Health and Human Services projections,
were a pandemic to occur, 200 million Americans could be infected, and
perhaps a half-million
would require hospitalization. If isolation and quarantine are unlikely
to be very effective, we will require a host of alternative protection
strategies,
ranging from emphasizing hand washing, providing N95 respirators, and reducing
social proximity, to preparing workplaces to keep employees at home, protecting
medical personnel and first responders, providing treatments, and expanding
hospital
and mortuary surge capacity in cities and states.

As
we undertake measures to reduce the risk of a pandemic and bolster
our ability to respond
if one does occur, developing an effective vaccine and
the capacity
to manufacture it in sufficient quantities must form the centerpiece
of our preparations. Other public health interventions can postpone
transmission
of the virus or mitigate
its effects, but vaccines are unique in their ability to prevent and
provide long-term protection against infection with a new strain of
influenza.
As
Anthony Fauci, the director of the National Institute of Allergy and
Infectious Diseases
(NIAID) put it, "The biggest challenge unequivocally is vaccine production
capacity." The U.S. can produce about 60 million doses of vaccine
for seasonal flu each year; the world can produce perhaps 300 million.
Yet the H5N1 vaccine
recently tested by NIAID required at least four times as much killed virus
to produce a satisfactory immune response as is normally used in vaccines.
That
means we could expect to make only 15 million doses in the U.S. and 75
million worldwide--far short of the need in a pandemic.

How can we
stretch this capacity? The single largest item in the president's
proposal is $2.8 billion to develop a vaccine-production system that
is cell-culture-based. Today, we make flu vaccines in chicken eggs, using
an approach that dates back
half a century and depends on adequate egg supplies and specialized equipment.
Developing a new technology to grow the vaccine seed strain in cell culture,
as other viral vaccine strains are grown, would be a major advance--one
that would speed vaccine production and expand capacity by allowing emergency
conversions of vaccine-production facilities from other viruses to influenza
in the event of a pandemic. However, this strategy will have a payoff
only in the medium- to long-term, at least five years from now.

LINKING
VACCINE STRATEGIES
In the short run, one promising approach that could expand our manufacturing
capacity is the use of adjuvant-containing vaccines. Adjuvants are chemical
additives that augment the immune response, allowing smaller doses of
vaccine to be effective
and the existing production capacity to yield more doses. An exciting
pilot study of an adjuvanted vaccine against influenza H5N3, a relative
of the
current avian
strain, showed that two doses together containing one-third as much antigen
as a normal flu vaccine, plus a novel adjuvant manufactured by one vaccine
company,
could produce a strong immune response. Equally important, this immune
response appeared to be broadly effective across a range of different
H5 viruses,
suggesting that the adjuvant could make a vaccine effective even if it
were not perfectly
matched against the precise emergent pandemic strain. Alum, an aluminum
salt that has been used as an adjuvant since the early 20th century,
also appears
to be an effective adjuvant in flu vaccines, and has the advantage of
having been licensed for many years for use in the U.S. Clinical trials
of adjuvanted
H5N1 vaccines are now under way, but additional trials and regulatory
hurdles must be cleared before such vaccines can be made ready for general
use.
If accelerated, this process could provide capacity to manufacture flu
vaccine
for nearly the
entire U.S., and could also stretch capacity to provide doses for a significant
proportion of the world. Careful clinical studies of vaccines with adjuvants
will be essential, however, since an adjuvant that produces too strong
an immune response to the infecting virus or an inappropriate immune
response could conceivably
increase pathology and exacerbate disease.

If we had a vaccine, how could
we get people to take it, given that less than a quarter of the U.S.
population receives seasonal flu vaccine in
a given year?
Indeed, even with a shortage, more unused seasonal flu vaccine was discarded
in 2005 than in 2004. One strategy for introducing a bird flu vaccine,
once we had a sufficient supply, would be to add it as a component of
our trivalent
seasonal
influenza vaccine. We do better against seasonal flu, immunologically
speaking, in part because we have already developed some immunity and
immunological
memory to related strains from previous years, which can then be boosted
by vaccines
or even by infection. We need to begin to prime our immune systems to
a newly emergent, related pandemic bird-flu strain, even if it is not
precisely
the
same as that which emerges as a pandemic.

Our annual seasonal flu vaccines
generally are composed of the three strains judged by WHO's expert
surveillance network as most likely to spread each year. In order to
begin to engender some level of immunity to bird-flu strains,
we propose to add to our regular seasonal influenza immunization program
a fourth strain, an H5N1 strain, after demonstrating its safety in volunteers.
If this
multivalent flu vaccine were efficiently deployed to all Americans, this
strategy would not only prevent many of the 36,000 deaths annually in
the U.S. from seasonal
flu and prime our immune systems against bird strains, but also enable
rapid scale-up of a specific vaccine strain when the pandemic strain
emerges and create
a credible market for industry.

Any new vaccine program against a pandemic
raises enormous ethical and regulatory questions. If supplies were limited,
who would be given vaccines?
First responders?
Politicians? Would enough vaccine be produced to protect people in developing
countries? How would its distribution be funded? Could adjuvanted vaccines
gain the same rapid FDA approval as standard seasonal vaccines to which
an H5N1 vaccine
could be added as simply an additional strain? Would companies have to
cut back on seasonal vaccine production to create capacity for a pandemic
strain?
In the
event of a major pandemic, would vaccination be made compulsory, as it
is in almost all states for children to attend school? And how would
these ethical
questions be resolved in a time of crisis?

As the tragic outcomes of the
1918 flu and hurricanes Katrina and Rita compellingly tell us, our tradition
of throwing money at the problem
only after a disaster
has occurred will not work with pandemic flu and other health emergencies.
This country, as well as every city and town, needs to prepare for a
pandemic in advance.
We at Harvard are doing our best to contribute our knowledge and skills
to this global effort--by modeling possible epidemiologic scenarios,
by collaborating with colleagues in Asia, by anticipating how to respond
to outbreaks of influenza,
and by training public health professionals in this country and abroad
to lead efforts to thwart the next pandemic.